# Endogenous and Environmental AHR Ligands in Head and Neck Cancer Aggression and Immunosuppression

> **NIH NIH R21** · BOSTON UNIVERSITY MEDICAL CAMPUS · 2020 · $206,250

## Abstract

The prognosis for the 60,000 Americans diagnosed each year with head and neck squamous cell carcinoma
(HNSCC) is grim with only 50%-60% of patients surviving 5 years. Surgery, radiation and chemotherapy are
debilitating. Immunotherapy shows promise but benefits only a minority of HNSCC patients. Thus, there is still
an unmet medical need to better understand the disease and to generate more effective targeted therapeutics.
Our exploratory study will address these two goals. Accumulating evidence indicates that the AHR is highly
expressed and chronically active in many cancers, including HNSCC, in the absence of xenobiotics (and
regardless of tumor etiology), by virtue of their production of endogenous AHR ligands including tryptophan-
derived metabolites in the Kynurenine (Kyn) pathway. Formation of these ligands is dependent on IDO or TDO
which themselves are AHR regulated, creating an AHR amplification loop. In negative feedback loops, AHR-
regulated CYP1A1 and CYP1B1 degrade endogenous ligands and AHR-regulated AHR repressor (AHRR)
suppresses AHR activity. We postulate that these elements of an “AHR circuit” contribute to a steady-state of
AHR activity which drives tumor aggression (e.g., cancer stem cell induction). Furthermore, we postulate that
these oncometabolites contribute to immunosuppression by polarizing AHR+ macrophages towards
immunosuppressive tumor-associated macrophages (TAMs), inducing granulocytic myeloid-derived
suppressor cells (MDSC-Gs), and/or skewing AHR+ T cells towards regulatory T cells (Tregs). Therefore, our
central hypothesis is that the AHR drives a self-sustaining AHR circuit that generates tryptophan metabolites
which enhance tumor aggressiveness and suppress tumor immunity. This hypothesis will be tested in two
specific aims: Aim 1: Determine the relative contribution of factors controlling steady-state AHR
signaling and Kyn production in human and murine HNSCC lines. AHR, IDO, TDO, CYP1A1, CYP1B1,
and AHRR will be systematically deleted and a postulated resetting of the AHR steady-state, along with its
biological consequences, assessed. The potential for environmental ligands to reset the steady-state also will
be determined. AHR circuit consequences of these perturbations will be used to advance a novel mathematical
model that, ultimately, can be used to describe and predict AHR activity and its biological consequences.
Aim 2: Determine at what level the AHR acts as an immune checkpoint regulator in HNSCC. The
hypothesis that malignant cells producing AHR ligand(s), by virtue of the AHR circuit (Aim 1), generate
immunosuppressive TAMs, MDSC-Gs, and/or Tregs will be tested using unique orthotopic models of murine
HNSCC and AHRLysM conditional knockout mice. In a translational subaim, we will pinpoint the immunologic
target (TAMs, MDSC-Gs, and/or Tregs) of our second generation, commercially licensed AHR inhibitor. These
interdisciplinary, collaborative studies will shed light on the dynamics of AHR ligand produ...

## Key facts

- **NIH application ID:** 9922302
- **Project number:** 5R21ES029624-02
- **Recipient organization:** BOSTON UNIVERSITY MEDICAL CAMPUS
- **Principal Investigator:** David H Sherr
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $206,250
- **Award type:** 5
- **Project period:** 2019-05-01 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9922302

## Citation

> US National Institutes of Health, RePORTER application 9922302, Endogenous and Environmental AHR Ligands in Head and Neck Cancer Aggression and Immunosuppression (5R21ES029624-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/9922302. Licensed CC0.

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